Tobacco use is the most important preventable cause of premature disability and death in the United States and in much of the world. In response to RFA-GM-04-002, we propose to create a Pharmacogenetics Research Network (PGRN) group to address pharmacogenetic questions related to nicotine addiction, an essential element of tobacco dependence, and treatment. The proposed Pharmacogenetics of Nicotine Addiction and Treatment (PNAT) program, consisting of Clinical, Genetics, Statistics, and Bioinformatics Cores, will conduct a series of multidisciplinary studies to investigate the genetic basis for both pharmacokinetic and pharmacodynamic aspects of nicotine as a drug of abuse, as well as individual variation in response to nicotine replacement therapy and bupropion as treatments for tobacco dependence. We also plan to carry out exploratory studies on varenicline and rimonabant, two novel smoking cessation medications currently under clinical development. The PNAT program has five goals: (1) To assess the independent and synergistic roles of candidate genes in nicotine metabolism, dependence and treatment outcome(s) by conducting genetic association analyses involving 5,061 participants in existing and prospectively recruited clinical populations. We will characterize both individual polymorphisms and haplotypes in the candidate genes, as well as gene-gene interactions. (2) To characterize the functional role of significantly associated genetic polymorphisms at molecular, cellular and animal model levels. (3) To clinically validate functionally significant genetic polymorphisms by conducting prospective genotype-stratified pharmacokinetic and pharmacodynamic studies. (4) To comprehensively evaluate the interaction of genetic factors and pharmacological interventions via pathway-based Bayesian hierarchical modeling. In addition to identification of population-level risk factors, we aim to ultimately use these models for the prediction of individual outcomes so as to design tailored pharmacological interventions within a smoking cessation treatment program. (5) To contribute informative pharmacogenetic data to the PharmGKB database and to create a shared research resource both for use by other members of the PGRN and by those in the communities focused on the understanding of tobacco dependence and, more broadly, drug addiction. The proposed research will lead to increased understanding of the genetic bases for nicotine addiction and genetic influences on responses to pharmacotherapy to aid smoking cessation. The long-term objective of this work is to better individualize treatment for tobacco dependence, to facilitate the development of novel medications, and to reduce the impact of smoking as a major health problem.